Basic Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Feb 26, 2020; 12(2): 152-167
Published online Feb 26, 2020. doi: 10.4252/wjsc.v12.i2.152
C-C chemokine receptor type 2-overexpressing exosomes alleviated experimental post-stroke cognitive impairment by enhancing microglia/macrophage M2 polarization
Huai-Chun Yang, Min Zhang, Rui Wu, Hai-Qing Zheng, Li-Ying Zhang, Jing Luo, Li-Li Li, Xi-Quan Hu
Huai-Chun Yang, Rui Wu, Hai-Qing Zheng, Li-Ying Zhang, Jing Luo, Li-Li Li, Xi-Quan Hu, Department of Rehabilitation Medicine, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
Min Zhang, Department of Andrology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
Author contributions: Hu XH, Yang HC, and Zhang M conceived and designed the experiments. Yang HC and Zhang M performed the experiments. Yang HC, Zhang M and Wu R acquired, analyzed and interpreted the data. Hu XH, Yang HC, and Zhang M wrote the manuscript. All authors have read and revised the final manuscript and approved it for publication.
Supported by the National Natural Science Foundation of China, No. 81871847 and No. 81672261.
Institutional review board statement: The study was reviewed and approved by the Institutional Animal Ethics Committee of Life Sciences School, Sun Yat-sen University.
Institutional animal care and use committee statement: Animal studies were reviewed and approved by the Institutional Animal Ethics Committee of Life Sciences School, Sun Yat-sen University.
Conflict-of-interest statement: The authors declare no conflicts of interest.
Data sharing statement: The data used to support the findings of this study are available from the corresponding author upon request.
ARRIVE guidelines statement: The manuscript has been prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Xi-Quan Hu, MD, PhD, Chief Physician, Professor, Department of Rehabilitation Medicine, the Third Affiliated Hospital, Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou 510000, Guangdong Province, China. sysu_hu@163.com
Received: October 22, 2019
Peer-review started: October 22, 2019
First decision: November 18, 2019
Revised: December 27, 2019
Accepted: January 19, 2020
Article in press: January 19, 2020
Published online: February 26, 2020
Processing time: 128 Days and 3.2 Hours
ARTICLE HIGHLIGHTS
Research background

Post-stroke cognitive impairment (PSCI) is a common sequela of stroke with considerable impact on the health well-being and quality of life to patients, and poses significant financial burden on society. Exosomes have been shown to possess therapeutic effects that are comparable to the mesenchymal stromal cells. However, few studies have focused on the effects of exosomes derived from human umbilical cord mesenchymal stem cells (HUC-MSCs) (ExoCtrl) on PSCI. Here in this study, we aimed to explore the if exosomes derived from C-C chemokine receptor type 2 (CCR2)-overexpressing HUC-MSCs (ExoCCR2) have any therapeutic effects on PSCI, and clarify the possible underlying mechanisms.

Research motivation

Effective treatment strategies for PSCI in stroke patients are an unmet clinical need.

Research objectives

In the present study, we aimed to: (1) Investigate whether CCR2 over-expressing exosomes possess improved therapeutic effects on PSCI; and (2) The possible underlying mechanisms involved in the therapeutic benefits of exosomes.

Research methods

The morphology of ExoCtrl and ExoCCR2 were determined by transmission electron microscopy and qNano® particles analyzer; the CCR2 expression in the ExoCtrl and ExoCCR2 was evaluated by Western blotting; the binding capacity of exosomes to CC chemokine ligand 2 (CCL2) in vivo was examined by ELISA; the effects of ExoCtrl and ExoCCR2 on PSCI in experimental stroke rats were assessed by Morris water maze. Remyelination and oligodendrogenesis was analyzed by Western blotting and immunofluorescence microscopy, and microglia/macrophage polarization were investigated by qRT-PCR and immunofluorescence imaging. The infiltration and activation of hematogenous macrophages were analyzed by transwell migration analysis and Western blotting.

Research results

CCR2-overexpressing HUC-MSCs could deliver CCR2 receptor rich exosomes. There were not significant difference in the size and morphology between ExoCtrl and ExoCCR2. ExoCCR2 showed more powerful binding capacity to CCL2, while ExoCtrl hardly bound to CCL2. ExoCCR2 enhanced the beneficial effects of ExoCtrl on PSCI through further promoting microglia/macrophage polarization-mediated oligodendrogenesis and remyelination. Compared with ExoCtrl, ExoCCR2 showed more powerful suppression on CCL2-induced macrophage migration and activation in vivo and in vitro.

Research conclusions

CCR2 over-expressing on exosomes showed enhanced therapeutic benefits on PSCI through more powerful modulation on microglia/macrophage polarization-mediated oligo-dendrogenesis and remyelination. The additional therapeutic effect maybe related to the suppression on CCL2-induced macrophage infiltration and activation.

Research perspectives

Our study provides great insight in the application of stem cells-based therapies for neural degenerative disorders. Comparisons of the therapeutic effects of ExoCtrl and ExoCCR2 on more clinically relevant animal models of stroke are warranted.